EP0585705A1 - Use of anti-TNF to treat bacterial meningitis - Google Patents

Use of anti-TNF to treat bacterial meningitis Download PDF

Info

Publication number
EP0585705A1
EP0585705A1 EP93113072A EP93113072A EP0585705A1 EP 0585705 A1 EP0585705 A1 EP 0585705A1 EP 93113072 A EP93113072 A EP 93113072A EP 93113072 A EP93113072 A EP 93113072A EP 0585705 A1 EP0585705 A1 EP 0585705A1
Authority
EP
European Patent Office
Prior art keywords
tnf
bacterial meningitis
meningitis
infection
bacterial
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP93113072A
Other languages
German (de)
French (fr)
Other versions
EP0585705B1 (en
Inventor
Richard F. Hector
Michael S. Collins
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Corp
Original Assignee
Bayer Corp
Miles Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Corp, Miles Inc filed Critical Bayer Corp
Publication of EP0585705A1 publication Critical patent/EP0585705A1/en
Application granted granted Critical
Publication of EP0585705B1 publication Critical patent/EP0585705B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241—Tumor Necrosis Factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • TNF tumor necrosis factor
  • the present application describes the unexpected findings that intravenous administration of a monoclonal antibody preparation to tumor necrosis factor several hours after initiation of fulminate bacterial meningitis augments the activity of antibiotics and leads to enhanced survival and improved clinical status of animals in comparison to animals treated with antibiotics alone.
  • Our method involves intravenous infusion of monoclonal antibodies that bind to TNF (anti-TNF) in an amount sufficient to treat a meningitis infection in a mammal.
  • a monoclonal anti-TNF is sufficient to neutralize the TNF produced by the mammal in response to the meningitis. It is thought that the treatment described herein is especially useful against Escherichia coli meningitis.
  • therapeutically effective amount means an amount, expressed as mg/kg body weight, sufficient to result in clinical improvement in the signs and symptoms of disease and/or prevention of mortality in the more critically ill mammal. That effective amount (or dose) ranges from about 1 mg/kg to 20 mg/kg mammal body weight, preferably about 15 mg/kg.
  • Pharmaceutically acceptable vehicle means a carrier suitable for delivery of safe and efficacious amounts of anti-TNF by the intravenous route.
  • Intravenously means injection directly into the blood circulatory system as done, for example, via venous or arterial routes (and as distinct from intracranial or spinal administration).
  • the monoclonal antibody preparation was a murine anti human TNF immunoglobulin G known as A10G10 expressed from a hybridoma cell line deposited with ATCC having Accession No. HB 9736.
  • Escherichia coli strain 050:K1 was employed in illustrative studies.
  • brain-heart infusion broth was inoculated from frozen stock cultures and allowed to grow two hours at 37°C.
  • the bacteria were collected by centrifugation, the pellet was washed and resuspended to the desired concentration.
  • a pig mammalian model of meningitis was used to assess the monoclonal anti-TNF in vivo.
  • 6 x 105 cfu for physiological assessment
  • 2 x 107 cfu for survival studies.
  • a total of eight pigs was infected, then divided into two groups of four each for testing.
  • TNF tumor necrosis factor
  • IL-6 interleuken 6
  • lactate glucose
  • glucose white blood cells
  • bacteria Both blood and spinal fluid were assessed for the concentration of anti-TNF to determine the degree of penetration of the immunoglobulin across the blood-brain barrier into the central nervous system. Results from the spinal fluid demonstrated that in pigs treated with the monoclonal anti-TNF, no detectable TNF was present. In contrast, pigs treated only with antibiotics had an average of 42 picograms per ml of TNF.
  • the spinal fluid from anti-TNF treated pigs had reduced levels (at least 77% reduction) of the cytokine IL-6, with an average of 2,747 units per ml, in comparison to control animals with an average of 12,087 units per ml.

Abstract

Bacterial meningitis infection in a mammal is treated by intravenous infusion of therapeutically effective amounts of monoclonal antibodies which bind to tumor necrosis factor alpha. Treatment can be initiated up to five hours after bacterial challenge and is preferably in combination with an antibiotic selected from cephalosporins and aminoglycosides.

Description

  • Field: This application is concerned generally with a treatment of infection and specifically with the use of monoclonal antibodies that bind to TNF to treat bacterial meningitis.
    Prior Art: Bacterial meningitis remains one of the more difficult management problems in clinical medicine. Evidence suggests that bacterial meningitis represents infection in a site with a reduced potential for host resistance. With essentially no antibodies or complement present in the spinal fluid, polymorphonucleocytes are essentially unable to contribute to the clearing of the intruding bacteria in the early steps of disease. Morbidity and mortality from bacterial meningitis remains high; a death rate of 30% for pneumococcal meningitis has not changed over the past 40 years despite new antibiotics and improved understanding of therapy practices. Bacterial meningitis is described in detail in Cecil, Textbook of Medicine, 19th addition at pages 1655-161, the details of which are incorporated into this application.
  • The role of tumor necrosis factor (TNF) in bacterial meningitis is described in an article by Arditi et al. in the Journal of Infectious Diseases, 162:p. 139-145(1990). See also related articles by Arditi et al., in the Journal of Infectious Diseases, vol. 160, no. 6, pp. 1005-1011, December 1989 and an article by Mustafa et al., the Journal of Infectious Diseases, vol. 160, no. 5, pp. 818-825, November 1989.
  • Recently, the role of cytokines in gram positive meningitis was described in an article by Saukkonen et al., the Journal of Experimental Medicine, Vol. 171, pp 439-448, February- 1990. In the above-cited article, polyclonal serum having antibodies that bind to TNF was delivered directly to the brain simultaneously with the microorganism initiating the meningitis.
  • Although current practices include rapid diagnostic procedures and aggressive treatment with the latest third-generation cephalosporins (among others), many patients fall victim to the disease despite the prompt sterilization of the cerebrospinal fluid. This unexpected outcome may result from harmful interactions between host cells and tissues and bacterial components released by treatment with lytic antibiotics (Scand. J. Infect., Dis. Supp. 74:173-179,1991). The burst of peptidoglycan, capsular polysaccharide and lipopolysaccharide liberated from the bacteria induce the production of a number of mediators including TNF in the central nervous system leading to meningeal and perivascular inflammation in the subarachnoid space. Disruption of the blood brain barrier ensures, leading to cerebral edema, ischemia, and a dramatic increase in intracranial pressure. Those that survive the acute phase of disease are often left with multiple neurological sequelae.
  • The lack of success with present clinical practices to reduce morbidity and mortality among victims of bacterial meningitis has led some investigators to experiment with procedures to reduce inflammation. Previous results from trails utilizing steroid-based anti-inflammatories either prior to or concomitant with antibiotic administration suggest that such an approach may have value. Mustafa et al., American Journal of Diseases of Children, Vol. 144, pp. 883-887, August 1990.
  • In other forms of life-threatening bacterial infections, most notably sepsis, the prevention of inflammation has been associated with a favorable outcome. Specifically, intervention with the production and activity of the proinflammatory-cytokine tumor necrosis factor has received considerable attention.
  • Treatment of experimentally-induced sepsis with antibiotics and antibodies capable of neutralizing tumor necrosis factor was found to result in a higher rate of survival in comparison to animals treated with antibiotics alone. However, for efficacy to be demonstrated in sepsis, it was necessary to infuse antibody to TNF within 30 min of bacterial or endotoxin challenge. See Mathison et al., Journal of Clinical Investigation, Vol. 81, pp. 1925-1937, June 1988, and also Hinshaw et al., Circulatory Shock, Vol 30, pp. 279-292, 1990.
  • Given the intravenous route of administration of this protein-based therapeutic, the likelihood of its usefulness in meningitis seemed small. This conclusion was based on the assumption of poor penetration of this macromolecule across the blood-brain barrier and restrictive timing of administration of the anti-tumor necrosis factor for the prevention of death due to sepsis under experimental conditions.
  • Indeed, the prior art teaches that administration of sufficient quantities of neutralizing antibodies to TNF must be done either prior to (Butler, Milsark, and Cerami, Science 229:869-871, 1985; Tracey et al., Nature 330:662-664, 1987) or concomitant with (Linshaw et al., Circ.Shock 30:279-292, 1990; Saukkonen et al., J. Exp. Med. 171:439-448, 1990) the endotoxin or bacterial challenge. Unlike the prior art, we found, quite surprisingly, that delay of treatment of up to five hours with anti-TNF monoclonal antibodies resulted in statistically significantly increased survival.
  • The present application describes the unexpected findings that intravenous administration of a monoclonal antibody preparation to tumor necrosis factor several hours after initiation of fulminate bacterial meningitis augments the activity of antibiotics and leads to enhanced survival and improved clinical status of animals in comparison to animals treated with antibiotics alone.
    • SUMMARY OF THE INVENTION
  • We have found that intravenous infusion of monoclonal antibodies to TNF are effective in treating a mammal having an infection of bacterial meningitis. Our method is effective up to at least five hours after infection and especially useful for the treatment of gram negative infections by augmentation of traditional anti-bacterial chemotherapy using antibiotics such as cephalosporins or aminoglycosides.
  • Our method involves intravenous infusion of monoclonal antibodies that bind to TNF (anti-TNF) in an amount sufficient to treat a meningitis infection in a mammal. In another embodiment a monoclonal anti-TNF is sufficient to neutralize the TNF produced by the mammal in response to the meningitis. It is thought that the treatment described herein is especially useful against Escherichia coli meningitis.
  • As used herein the term therapeutically effective amount (of monoclonal anti-TNF) means an amount, expressed as mg/kg body weight, sufficient to result in clinical improvement in the signs and symptoms of disease and/or prevention of mortality in the more critically ill mammal. That effective amount (or dose) ranges from about 1 mg/kg to 20 mg/kg mammal body weight, preferably about 15 mg/kg.
  • Pharmaceutically acceptable vehicle means a carrier suitable for delivery of safe and efficacious amounts of anti-TNF by the intravenous route.
  • Intravenously means injection directly into the blood circulatory system as done, for example, via venous or arterial routes (and as distinct from intracranial or spinal administration).
    • SPECIFIC EMBODIMENTS
  • The Anti-TNF Preparation: In the examples below, the monoclonal antibody preparation was a murine anti human TNF immunoglobulin G known as A10G10 expressed from a hybridoma cell line deposited with ATCC having Accession No. HB 9736.
    • Strains and conditions of culture
  • Escherichia coli strain 050:K1 was employed in illustrative studies. For the growth of bacteria, brain-heart infusion broth was inoculated from frozen stock cultures and allowed to grow two hours at 37°C. The bacteria were collected by centrifugation, the pellet was washed and resuspended to the desired concentration.
    • In vivo studies
  • A pig mammalian model of meningitis was used to assess the monoclonal anti-TNF in vivo. Outbred Chester-White pigs, weighing 8-11 kg., were anesthetized, then infected intracisternally with either 6 x 10⁵ cfu (for physiological assessment) or 2 x 10⁷ cfu (for survival studies). For physiological studies, a total of eight pigs was infected, then divided into two groups of four each for testing. For survival studies, a total of 26 pigs were infected and divided into two groups of 13 each for testing.
  • For physiological studies, three hours after infection pigs were again anesthetized. One group was given 15 mg/kg of the monoclonal anti-TNF via intravenous infusion in an ear vein, while the other group was given placebo (consisting of the pharmaceutical vehicle). Also, all animals were given 5 mg/kg of gentamicin sulfate intramuscularly three hours after infection. Six hours after infection (and three hours after treatment) the pigs were again anesthetized and blood and cerebral spinal fluid was removed for study.
  • For survival studies, five hours after infection pigs were anesthetized. One group was given 15 mg/kg of the monoclonal anti-TNF via intravenous infusion in an ear vein, while the other group was given placebo (consisting of the pharmaceutical vehicle). All animals were given 75 mg/kg of ceftriaxone intramuscularly. Surviving animals were given subsequent 50 mg/kg doses of ceftriaxone 24 and 48 hours after infection. Animals in this experiment were observed for mortalities for seven days.
    • Results: Physiological studies
  • Cerebral spinal fluid from the animals was assessed for presence of tumor necrosis factor (TNF), interleuken 6 (IL-6), lactate, glucose, white blood cells, and bacteria. Both blood and spinal fluid were assessed for the concentration of anti-TNF to determine the degree of penetration of the immunoglobulin across the blood-brain barrier into the central nervous system. Results from the spinal fluid demonstrated that in pigs treated with the monoclonal anti-TNF, no detectable TNF was present. In contrast, pigs treated only with antibiotics had an average of 42 picograms per ml of TNF. Also, the spinal fluid from anti-TNF treated pigs had reduced levels (at least 77% reduction) of the cytokine IL-6, with an average of 2,747 units per ml, in comparison to control animals with an average of 12,087 units per ml.
  • Animals treated with the anti-TNF monoclonal antibodies did not have discernible differences in pleocytosis, lactate, glucose, or reduced numbers of bacteria in comparison to controls. These results are summarized in Table I below. TABLE I
    RESULTS OF SPINAL FLUID DETERMINATIONS
    GROUP TNF pg/ml IL-6 units/ml LACTATE mg/100 ml GLUCOSE WBC BACTERIA CFU/ml
    mg/100 ml x 10e6/ml
    Control 41.5±8.5 12,087 5.0±.2 83±11 4.00±2 5.62x10e4
    Anti-TNF <5 2,747 4.3±.1 95±2 5.07±.09 3.18x10e5

    The average penetration of the monoclonal anti-TNF into the cerebral spinal fluid was determined to be 4.5% of serum values.
    • Survival Studies:
  • Deaths in the control group, treated with ceftriaxone only, had rapid onset, reaching 77% 24 hours after infection. In contrast, in pigs treated with the monoclonal anti-TNF and ceftriaxone, deaths accounted for only 15% of the total 24 hours after infection. By the end of the experiment, seven days after infection, 92% of control animals had died while only 38% of the monoclonal anti-TNF group had died. The results are summarized in the Table II below. TABLE II
    SURVIVAL RESULTS
    TREATMENT GROUP DEAD/TOTAL AT INTERVAL
    24h 48h 7 days
    Control 10/13 10/13 12/13
    Anti-TNF 2/13 4/13 5/13
    • Discussion
  • The data indicate that monoclonal anti-TNF, when used in conjunction with antibiotics, can serve as an efficacious agent in established bacterial meningitis infections. In a surprising finding, the physiologic study indicated that the intravenous administration of monoclonal anti-TNF in animals infected with Escherichia coli in the central nervous system can lead to the neutralization of TNF in the cerebral spinal fluid, and results in the reduced production of the cytokine IL-6.
  • In the survival experiments, the results indicated that animals (mammals) infected with a potentially lethal challenge of Escherichia coli in the central nervous system can be protected by intravenously-administered monoclonal anti-TNF in combination with an antibiotic, and that this protection is evident for a period of at least seven days after infection. Therefore, it is thought that this agent should be considered as a therapeutic agent in human use for the described bacterial meningitis as well as for other medically important bacteria capable of causing this disease.
  • Given the active disclosure it is thought that variations of treatment will occur to those skilled in treatment of infectious diseases. Accordingly, it is intended that the above examples should be construed as illustrative and the invention disclosed here should be limited only by the following claims.

Claims (6)

  1. Use of monoclonal antibodies which bind to tumor necrosis factor for the preparation of medicaments for the treatment of bacterial meningitis infections.
  2. Use according to claim 1 wherein the medicament additionally comprises an antibiotic.
  3. Use according to claim 2 wherein the antibiotic is selected from the group consisting of cephalosporins and aminoglycosides.
  4. Use according to any of claim 1 to 3 wherein the antibodies are included in a pharmaceutically acceptable vehicle.
  5. Use according to any of claims 2 to 4 wherein the antibiotic is selected from ceftriaxone and gentamicin.
  6. Use according to any of claims 1 to 5 wherein the antibody is expressed from a hybridoma having an ATCC Accession No. HB 9736.
EP93113072A 1992-08-28 1993-08-16 Use of monoclonal antibodies to TNF to treat bacterial meningitis Expired - Lifetime EP0585705B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US93793992A 1992-08-28 1992-08-28
US937939 1992-08-28

Publications (2)

Publication Number Publication Date
EP0585705A1 true EP0585705A1 (en) 1994-03-09
EP0585705B1 EP0585705B1 (en) 1998-11-04

Family

ID=25470604

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93113072A Expired - Lifetime EP0585705B1 (en) 1992-08-28 1993-08-16 Use of monoclonal antibodies to TNF to treat bacterial meningitis

Country Status (6)

Country Link
US (1) US5616321A (en)
EP (1) EP0585705B1 (en)
AT (1) ATE172880T1 (en)
DE (1) DE69321909T2 (en)
DK (1) DK0585705T3 (en)
ES (1) ES2121907T3 (en)

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0614984A2 (en) † 1993-03-05 1994-09-14 Bayer Corporation Human anti-TNF antibodies
WO2004016286A2 (en) 2002-08-16 2004-02-26 Abbott Biotechnology Ltd. Pharmaceutical anti-tnf-alpha antibody formulation
US6790444B2 (en) 1991-03-18 2004-09-14 New York University Medical Center Anti-TNF antibodies and peptides of human necrosis factor
WO2005110452A2 (en) 2004-04-09 2005-11-24 Abbott Biotechnology Ltd. MULTIPLE-VARIABLE DOSE REGIMEN FOR TREATING TNFα-RELATED DISORDERS
US7101674B2 (en) 1991-03-18 2006-09-05 New York University Anti-idiotypic anti-TNF antibodies and related immunoassay methods
US7128908B2 (en) 1991-03-18 2006-10-31 Centocor, Inc. Methods for treating systemic lupus erythematosus using anti-TNF antibodies and fragments thereof
EP2196218A2 (en) 2002-04-26 2010-06-16 Abbott Biotechnology Ltd Use of anti-TNFalpha antibodies and another drug
EP2295071A1 (en) 2002-10-24 2011-03-16 Abbott Biotechnology Ltd Low dose methods for treating disorders in which TNF-alpha activity is detrimental
EP2305712A1 (en) 1996-02-09 2011-04-06 Abbott Biotechnology Ltd Human antibodies that bind human TNFalpha
EP2324851A1 (en) 2001-06-08 2011-05-25 Abbott Biotechnology Ltd Methods of administering anti-TNFalpha antibodies
EP2365000A2 (en) 2005-05-18 2011-09-14 Ablynx N.V. Improved nanobodiesTM against tumor necrosis factor-alpha
EP2390268A1 (en) 2002-11-08 2011-11-30 Ablynx N.V. Single domain antibodies directed against tumour necrosis factor-alpha and uses therefor
WO2012177778A1 (en) 2011-06-20 2012-12-27 Mount Sinai School Of Medicine Anti-tnf- therapy for the mucopolysaccharidoses and other lysosomal disorders
EP2738179A1 (en) 2006-04-05 2014-06-04 AbbVie Biotechnology Ltd Antibody purification
EP2803365A1 (en) 2013-05-14 2014-11-19 Commissariat A L'energie Atomique Et Aux Energies Alternatives Use of clonazepam in combination with antibiotic in the treatment of bacterially induced meningitis
US8986693B1 (en) 2004-04-09 2015-03-24 Abbvie Biotechnology Ltd. Use of TNFα inhibitor for treatment of psoriasis
WO2015073884A2 (en) 2013-11-15 2015-05-21 Abbvie, Inc. Glycoengineered binding protein compositions
US9365645B1 (en) 2011-04-27 2016-06-14 Abbvie, Inc. Methods for controlling the galactosylation profile of recombinantly-expressed proteins
WO2016160976A2 (en) 2015-03-30 2016-10-06 Abbvie Inc. Monovalent tnf binding proteins
EP3078675A1 (en) 2015-04-10 2016-10-12 Ares Trading S.A. Induction dosing regimen for the treatment of tnf alpha mediated disorders
US9499614B2 (en) 2013-03-14 2016-11-22 Abbvie Inc. Methods for modulating protein glycosylation profiles of recombinant protein therapeutics using monosaccharides and oligosaccharides
US9499616B2 (en) 2013-10-18 2016-11-22 Abbvie Inc. Modulated lysine variant species compositions and methods for producing and using the same
US9505833B2 (en) 2012-04-20 2016-11-29 Abbvie Inc. Human antibodies that bind human TNF-alpha and methods of preparing the same
US9512214B2 (en) 2012-09-02 2016-12-06 Abbvie, Inc. Methods to control protein heterogeneity
US9522953B2 (en) 2013-10-18 2016-12-20 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same
US9598667B2 (en) 2013-10-04 2017-03-21 Abbvie Inc. Use of metal ions for modulation of protein glycosylation profiles of recombinant proteins
US9605064B2 (en) 2006-04-10 2017-03-28 Abbvie Biotechnology Ltd Methods and compositions for treatment of skin disorders
US9683033B2 (en) 2012-04-20 2017-06-20 Abbvie, Inc. Cell culture methods to reduce acidic species
US9688752B2 (en) 2013-10-18 2017-06-27 Abbvie Inc. Low acidic species compositions and methods for producing and using the same using displacement chromatography
US9708400B2 (en) 2012-04-20 2017-07-18 Abbvie, Inc. Methods to modulate lysine variant distribution
US9708399B2 (en) 2013-03-14 2017-07-18 Abbvie, Inc. Protein purification using displacement chromatography
WO2018124948A1 (en) 2016-12-30 2018-07-05 Закрытое Акционерное Общество "Биокад" AQUEOUS PHARMACEUTICAL COMPOSITION OF A RECOMBINANT MONOCLONAL ANTIBODY TO FNOα
US10465003B2 (en) 2016-02-05 2019-11-05 Janssen Biotech, Inc. Anti-TNF antibodies, compositions, methods and use for the treatment or prevention of type 1 diabetes

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI334439B (en) 2001-08-01 2010-12-11 Centocor Inc Anti-tnf antibodies, compositions, methods and uses
MXPA05005921A (en) * 2002-12-02 2005-10-19 Abgenix Inc Antibodies directed to tumor necrosis factor and uses thereof.
US7101978B2 (en) * 2003-01-08 2006-09-05 Applied Molecular Evolution TNF-α binding molecules
JP4484664B2 (en) * 2003-11-27 2010-06-16 キヤノン株式会社 Recording head cartridge
US7435799B2 (en) * 2004-01-08 2008-10-14 Applied Molecular Evolution TNF-α binding molecules
CA2898354C (en) 2013-01-25 2017-11-21 Thymon, Llc Compositions for selective reduction of circulating bioactive soluble tnf and methods for treating tnf-mediated disease

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990000902A1 (en) * 1988-07-18 1990-02-08 Chiron Corporation Monoclonal antibodies reactive with cachectin
WO1990001950A1 (en) * 1988-08-19 1990-03-08 Celltech Limited Pharmaceutical products for anti-neoplastic therapy
WO1992003145A1 (en) * 1990-08-27 1992-03-05 Peptide Technology Ltd. Method of treating viral infection

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL73883A (en) * 1984-12-20 1990-12-23 Yeda Res & Dev Monoclonal antibodies against tnf-alpha,hybridomas producing them and method for the purification of tnf-alpha
DE3631229A1 (en) * 1986-09-13 1988-03-24 Basf Ag MONOCLONAL ANTIBODIES AGAINST HUMAN TUMORNESCROSE FACTOR (TNF) AND THEIR USE
EP0288088B1 (en) * 1987-04-24 1994-03-09 Teijin Limited Detection of tumor necrosis factor; monoclonal antibody and kit
GB8806339D0 (en) * 1988-03-17 1988-04-13 Hoffmann La Roche Monoclonal antibodies
US5360716A (en) * 1988-10-24 1994-11-01 Otsuka Pharmaceutical Co., Ltd. Human tumor necrosis factor αspecific monoclonal antibody and method for detecting human tumor necrosis factor α
GB8905400D0 (en) * 1989-03-09 1989-04-19 Jonker Margreet Medicaments
GB8921123D0 (en) * 1989-09-19 1989-11-08 Millar Ann B Treatment of ards
GB9028123D0 (en) * 1990-12-28 1991-02-13 Erba Carlo Spa Monoclonal antibodies against human tumor necrosis factor alpha
ES2156859T5 (en) * 1991-03-18 2008-03-16 New York University SPECIFIC MONOCLONAL AND CHEMICAL ANTIBODIES FOR THE HUMAN TUMOR NECROSIS FACTOR.
WO1994008619A1 (en) * 1992-10-08 1994-04-28 The Kennedy Institute Of Rheumatology Treatment of autoimmune and inflammatory disorders
GB9225448D0 (en) * 1992-12-04 1993-01-27 Erba Carlo Spa Improved synthesis of polymer bioactive conjugates
WO1995015179A1 (en) * 1993-12-01 1995-06-08 Unisearch Limited Method of treating intestinal disorders

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990000902A1 (en) * 1988-07-18 1990-02-08 Chiron Corporation Monoclonal antibodies reactive with cachectin
WO1990001950A1 (en) * 1988-08-19 1990-03-08 Celltech Limited Pharmaceutical products for anti-neoplastic therapy
WO1992003145A1 (en) * 1990-08-27 1992-03-05 Peptide Technology Ltd. Method of treating viral infection

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
THIERRY CALANDRA ET AL.: "ANTI-LIPOPOLYSACCHARIDE AND ANTI-TUMOR NECROSIS FACTOR/CACHECTIN ANTIBODIES FOR THE TREATMENT OF GRAM-NEGATIVE BACTEREMIA AND SEPTIC SHOCK.", PROGR.CLIN. BIOL. RES., vol. 367, 1991, pages 141 - 159 *

Cited By (100)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7227003B2 (en) 1991-03-18 2007-06-05 New York University Anti-TNF antibody fragments
US7101674B2 (en) 1991-03-18 2006-09-05 New York University Anti-idiotypic anti-TNF antibodies and related immunoassay methods
US6790444B2 (en) 1991-03-18 2004-09-14 New York University Medical Center Anti-TNF antibodies and peptides of human necrosis factor
US6835823B2 (en) 1991-03-18 2004-12-28 New York University Anti-TNF antibodies and peptides of human tumor necrosis factor
US7744885B2 (en) 1991-03-18 2010-06-29 Centocor, Inc. Methods of treating vascular inflammatory pathology using anti-TNF antibodies and fragments thereof
US7070775B2 (en) 1991-03-18 2006-07-04 New York University Recombinant A2-specific TNFα specific antibodies
US7226593B2 (en) 1991-03-18 2007-06-05 Centocor, Inc. Methods of treating cachexia with chimeric anti-TNF antibodies
US7128908B2 (en) 1991-03-18 2006-10-31 Centocor, Inc. Methods for treating systemic lupus erythematosus using anti-TNF antibodies and fragments thereof
US7128907B2 (en) 1991-03-18 2006-10-31 Centocor, Inc. Methods of treating crohn's disease with anti-TNF antibodies
US7135178B2 (en) 1991-03-18 2006-11-14 Centocor, Inc. Methods of treating disseminated intravascular coagulation using anti-TNF antibodies
US7135179B2 (en) 1991-03-18 2006-11-14 Centocor, Inc. Methods for treating sarcoidosis using anti-TNF antibodies and fragments thereof
US7252823B2 (en) 1991-03-18 2007-08-07 Centocor, Inc. Recombinant A2-specific TNFα-specific antibodies
US7160542B2 (en) 1991-03-18 2007-01-09 New York University Method of treating psoriasis using human anti-TNF antibodies and fragments
US7160543B2 (en) 1991-03-18 2007-01-09 New York University Methods of inhibiting TNF-α in patients with Crohn's disease
US7160995B2 (en) 1991-03-18 2007-01-09 New York University DNA encoding anti-TNF antibodies and peptides
US7166284B2 (en) 1991-03-18 2007-01-23 New York University Methods of treating joint inflammation with anti-TNF antibodies
US7169388B2 (en) 1991-03-18 2007-01-30 New York University Methods of inhibiting TNFα in patients with cancer
US7169386B1 (en) 1991-03-18 2007-01-30 New York University Methods of treating inflammation associated with viral infection with anti-TNF antibodies
US7179893B2 (en) 1991-03-18 2007-02-20 New York University Recombinant anti-TNF-α antibodies
US7179466B2 (en) 1991-03-18 2007-02-20 New York University Methods of treating rheumatoid arthritis by multiple administration of anti-TNF antibodies
US7425330B2 (en) 1991-03-18 2008-09-16 Centocor, Inc. Methods of inhibiting TNFα activity in the blood of a patient
US7204985B2 (en) 1991-03-18 2007-04-17 Centocor, Inc. Methods of treating disseminated intravascular coagulation by multiple administration of anti-TNF antibodies
US7214376B2 (en) 1991-03-18 2007-05-08 New York University Methods of inhibiting TNFα in patients with neoplastic disease
US7223396B2 (en) 1991-03-18 2007-05-29 Centocor, Inc. Methods of treatment of fistulas in Crohn's disease with anti-TNF antibodies
US7192584B2 (en) 1991-03-18 2007-03-20 Centocor, Inc. Methods of treating psoriasis with anti-TNF antibodies
US7416729B2 (en) 1991-03-18 2008-08-26 Centocor, Inc. Methods of treating rheumatoid arthritis with anti-TNF antibodies
US7138118B2 (en) 1991-03-18 2006-11-21 Centocor, Inc. Methods of treating rheumatoid arthritis with anti-TNF antibodies
US7276239B2 (en) 1991-03-18 2007-10-02 Centocor, Inc. Recombinant A2-specific TNFα-specific antibodies
US7335358B2 (en) 1991-03-18 2008-02-26 Centocor, Inc. Methods of treating psoriasis with anti-TNF antibodies
US7374761B2 (en) 1991-03-18 2008-05-20 Centocor, Inc. Recombinant A2-specific TNFα-specific antibodies
US7404955B2 (en) 1991-03-18 2008-07-29 Centocor, Inc. Methods of inhibiting or neutralizing TNFα in patients with tissue injury
EP0614984B2 (en) † 1993-03-05 2010-11-03 Bayer HealthCare LLC Anti-TNF alpha human monoclonal antibodies
EP0614984A2 (en) † 1993-03-05 1994-09-14 Bayer Corporation Human anti-TNF antibodies
EP2930186A1 (en) 1996-02-09 2015-10-14 AbbVie Biotechnology Ltd Human antibodies that bind human tnfalpha
EP2305713A1 (en) 1996-02-09 2011-04-06 Abbott Biotechnology Ltd Human antibodies that bind human TNFalpha
EP2397494A1 (en) 1996-02-09 2011-12-21 Abbott Biotechnology Ltd Human antibodies that bind human TNFalpha
EP2357200A1 (en) 1996-02-09 2011-08-17 Abbott Biotechnology Ltd Human antibodies that bind human TNFalpha
EP2933267A1 (en) 1996-02-09 2015-10-21 AbbVie Biotechnology Ltd Human antibodies that bind human tnfalpha
EP2305712A1 (en) 1996-02-09 2011-04-06 Abbott Biotechnology Ltd Human antibodies that bind human TNFalpha
EP2930185A1 (en) 1996-02-09 2015-10-14 AbbVie Biotechnology Ltd Human antibodies that bind human tnfalpha
EP2930187A1 (en) 1996-02-09 2015-10-14 AbbVie Biotechnology Ltd Human antibodies that bind human tnfalpha
EP2364731A2 (en) 2001-06-08 2011-09-14 Abbott Biotechnology Ltd Methods of administering anti-TNFalpha antibodies
EP3190124A1 (en) 2001-06-08 2017-07-12 AbbVie Biotechnology Ltd Adalimumab for use in therapy of rheumatoid arthritis
EP2940044A1 (en) 2001-06-08 2015-11-04 AbbVie Biotechnology Ltd Methods of administering anti-tnfalpha antibodies
EP2359855A2 (en) 2001-06-08 2011-08-24 Abbott Biotechnology Ltd Methods of administering anti-TNFalpha antibodies
EP2324851A1 (en) 2001-06-08 2011-05-25 Abbott Biotechnology Ltd Methods of administering anti-TNFalpha antibodies
EP2347766A1 (en) 2002-04-26 2011-07-27 Abbott Biotechnology Ltd Use of TNFalpha antibodies and another drug
EP2196218A2 (en) 2002-04-26 2010-06-16 Abbott Biotechnology Ltd Use of anti-TNFalpha antibodies and another drug
US9090689B1 (en) 2002-07-19 2015-07-28 Abbvie Biotechnology Ltd. Use of TNFα inhibitor for treatment of psoriasis
EP2363145A1 (en) 2002-08-16 2011-09-07 Abbott Biotechnology Ltd Pharmaceutical anti-TNF-alpha antibody formulation
US9950066B2 (en) 2002-08-16 2018-04-24 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
EP2363144A1 (en) 2002-08-16 2011-09-07 Abbott Biotechnology Ltd Pharmaceutical anti-TNF-alpha antibody formulation
EP2361637A1 (en) 2002-08-16 2011-08-31 Abbott Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
EP2359856A1 (en) 2002-08-16 2011-08-24 Abbott Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
WO2004016286A2 (en) 2002-08-16 2004-02-26 Abbott Biotechnology Ltd. Pharmaceutical anti-tnf-alpha antibody formulation
US9732152B2 (en) 2002-08-16 2017-08-15 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9738714B2 (en) 2002-08-16 2017-08-22 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9750808B2 (en) 2002-08-16 2017-09-05 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-alpha associated disorders
EP2295071A1 (en) 2002-10-24 2011-03-16 Abbott Biotechnology Ltd Low dose methods for treating disorders in which TNF-alpha activity is detrimental
EP2332565A1 (en) 2002-10-24 2011-06-15 Abbott Biotechnology Ltd. Low dose methods for treating disorders in which TNFalpha activity is detrimental
EP2390268A1 (en) 2002-11-08 2011-11-30 Ablynx N.V. Single domain antibodies directed against tumour necrosis factor-alpha and uses therefor
EP3299393A1 (en) 2002-11-08 2018-03-28 Ablynx N.V. Single domain antibodies directed against tumour necrosis factor-alpha and uses therefor
EP2335731A2 (en) 2004-04-09 2011-06-22 Abbott Biotechnology Ltd Multiple-variable dose regimen for treating TNF-alpha-related disorders
US8889136B2 (en) 2004-04-09 2014-11-18 Abbvie Biotechnology Ltd. Multiple-variable dose regimen for treating TNFα-related disorders
US9512216B2 (en) 2004-04-09 2016-12-06 Abbvie Biotechnology Ltd. Use of TNFα inhibitor
EP2335732A2 (en) 2004-04-09 2011-06-22 Abbott Biotechnology Ltd Multiple-variable dose regimen for treating TNF-alpha-related disorders
US8986693B1 (en) 2004-04-09 2015-03-24 Abbvie Biotechnology Ltd. Use of TNFα inhibitor for treatment of psoriasis
EP2338516A2 (en) 2004-04-09 2011-06-29 Abbott Biotechnology Ltd Multiple-variable dose regimen for treating TNF-alpha-related disorders
WO2005110452A2 (en) 2004-04-09 2005-11-24 Abbott Biotechnology Ltd. MULTIPLE-VARIABLE DOSE REGIMEN FOR TREATING TNFα-RELATED DISORDERS
EP3613767A1 (en) 2005-05-18 2020-02-26 Ablynx N.V. Improved nanobodiestm against tumor cecrosis factor-alpha
EP2949668A1 (en) 2005-05-18 2015-12-02 Ablynx N.V. Improved nanobodiestm against tumor necrosis factor-alpha
EP2479191A2 (en) 2005-05-18 2012-07-25 Ablynx N.V. Improved nanobodiesTM against tumor necrosis factor-alpha
EP2365000A2 (en) 2005-05-18 2011-09-14 Ablynx N.V. Improved nanobodiesTM against tumor necrosis factor-alpha
EP2738178A1 (en) 2006-04-05 2014-06-04 AbbVie Biotechnology Ltd Antibody purification
EP2738179A1 (en) 2006-04-05 2014-06-04 AbbVie Biotechnology Ltd Antibody purification
EP3088410A2 (en) 2006-04-05 2016-11-02 AbbVie Biotechnology Ltd Antibody purification
US9605064B2 (en) 2006-04-10 2017-03-28 Abbvie Biotechnology Ltd Methods and compositions for treatment of skin disorders
US9365645B1 (en) 2011-04-27 2016-06-14 Abbvie, Inc. Methods for controlling the galactosylation profile of recombinantly-expressed proteins
US9505834B2 (en) 2011-04-27 2016-11-29 Abbvie Inc. Methods for controlling the galactosylation profile of recombinantly-expressed proteins
WO2012177778A1 (en) 2011-06-20 2012-12-27 Mount Sinai School Of Medicine Anti-tnf- therapy for the mucopolysaccharidoses and other lysosomal disorders
US9683033B2 (en) 2012-04-20 2017-06-20 Abbvie, Inc. Cell culture methods to reduce acidic species
US9708400B2 (en) 2012-04-20 2017-07-18 Abbvie, Inc. Methods to modulate lysine variant distribution
US9957318B2 (en) 2012-04-20 2018-05-01 Abbvie Inc. Protein purification methods to reduce acidic species
US9505833B2 (en) 2012-04-20 2016-11-29 Abbvie Inc. Human antibodies that bind human TNF-alpha and methods of preparing the same
US9512214B2 (en) 2012-09-02 2016-12-06 Abbvie, Inc. Methods to control protein heterogeneity
US9708399B2 (en) 2013-03-14 2017-07-18 Abbvie, Inc. Protein purification using displacement chromatography
US9499614B2 (en) 2013-03-14 2016-11-22 Abbvie Inc. Methods for modulating protein glycosylation profiles of recombinant protein therapeutics using monosaccharides and oligosaccharides
EP2803365A1 (en) 2013-05-14 2014-11-19 Commissariat A L'energie Atomique Et Aux Energies Alternatives Use of clonazepam in combination with antibiotic in the treatment of bacterially induced meningitis
US9598667B2 (en) 2013-10-04 2017-03-21 Abbvie Inc. Use of metal ions for modulation of protein glycosylation profiles of recombinant proteins
US9522953B2 (en) 2013-10-18 2016-12-20 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same
US9688752B2 (en) 2013-10-18 2017-06-27 Abbvie Inc. Low acidic species compositions and methods for producing and using the same using displacement chromatography
US9499616B2 (en) 2013-10-18 2016-11-22 Abbvie Inc. Modulated lysine variant species compositions and methods for producing and using the same
WO2015073884A2 (en) 2013-11-15 2015-05-21 Abbvie, Inc. Glycoengineered binding protein compositions
US9550826B2 (en) 2013-11-15 2017-01-24 Abbvie Inc. Glycoengineered binding protein compositions
WO2016160976A2 (en) 2015-03-30 2016-10-06 Abbvie Inc. Monovalent tnf binding proteins
WO2016162537A1 (en) 2015-04-10 2016-10-13 Ares Trading S.A Induction dosing regimen
EP3078676A1 (en) 2015-04-10 2016-10-12 Ares Trading S.A. Induction dosing regimen for the treatment of tnf alpha mediated disorders
EP3078675A1 (en) 2015-04-10 2016-10-12 Ares Trading S.A. Induction dosing regimen for the treatment of tnf alpha mediated disorders
US10465003B2 (en) 2016-02-05 2019-11-05 Janssen Biotech, Inc. Anti-TNF antibodies, compositions, methods and use for the treatment or prevention of type 1 diabetes
WO2018124948A1 (en) 2016-12-30 2018-07-05 Закрытое Акционерное Общество "Биокад" AQUEOUS PHARMACEUTICAL COMPOSITION OF A RECOMBINANT MONOCLONAL ANTIBODY TO FNOα

Also Published As

Publication number Publication date
ES2121907T3 (en) 1998-12-16
DK0585705T3 (en) 1999-07-26
US5616321A (en) 1997-04-01
DE69321909D1 (en) 1998-12-10
DE69321909T2 (en) 1999-04-01
ATE172880T1 (en) 1998-11-15
EP0585705B1 (en) 1998-11-04

Similar Documents

Publication Publication Date Title
EP0585705B1 (en) Use of monoclonal antibodies to TNF to treat bacterial meningitis
US5593665A (en) Pharmaceutical compositions
Lee et al. Fluid replacement protection of rabbits challenged subcutaneous with toxic shock syndrome toxins
CN1269727A (en) Pharmaceutical compositions containing lyosostaphin alone or in combination with antibiotic for treatment of staphylococcal infections
JPH0586379B2 (en)
Cross et al. The efficacy of combination immunotherapy in experimental Pseudomonas sepsis
US6720011B1 (en) Injectable composition for cancer treatment
Holmes et al. Cinoxacin: effectiveness against experimental pyelonephritis in rats
AT397615B (en) MEDICINAL PRODUCT PROTEIN C
CA2122596C (en) Treatment of neurological conditions by an interleukin-1 inhibiting compound
Barg et al. Persistent staphylococcal bacteremia in an intravenous drug abuser
JPS63101330A (en) Treating method for infections disease
US6132715A (en) Method of inhibiting biosynthesis of tumor necrosis factor
Tripodi et al. Successful treatment with ampicillin and fluoroquinolones of human endocarditis due to high-level gentamicin-resistant enterococci
EP3541407A1 (en) Combined cd6 and imipenem therapy for treatment of infectious diseases and related inflammatory processes
Bradsher Relapse of gram-negative bacillary meningitis after cefotaxime therapy
JP2012517472A (en) Composition for treating sepsis comprising reduced genome bacteria
Stoltz et al. Use of granulocyte colony-stimulating factor in the treatment of acute infectious diseases
EP0791360A2 (en) Treatment of septic shock with anti-TNF antibodies
CA2485882C (en) A therapeutic agent for mycobacterium tuberculosis comprising 15k granulysin as the active ingredient
JP2002529515A5 (en)
US20140162958A1 (en) Copolymer-1 Composition and Methods of Use
Dutcher The potential benefit of granulocyte transfusion therapy
Alexander Some immunologically based reactions that can cause the regression of large tumor masses
TW518229B (en) Prophylaxis and/or treatment agent for septicemia

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE

17P Request for examination filed

Effective date: 19940819

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BAYER CORPORATION

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BAYER CORPORATION

17Q First examination report despatched

Effective date: 19970303

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BAYER CORPORATION

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE

REF Corresponds to:

Ref document number: 172880

Country of ref document: AT

Date of ref document: 19981115

Kind code of ref document: T

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: E. BLUM & CO. PATENTANWAELTE

Ref country code: CH

Ref legal event code: EP

REF Corresponds to:

Ref document number: 69321909

Country of ref document: DE

Date of ref document: 19981210

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2121907

Country of ref document: ES

Kind code of ref document: T3

ET Fr: translation filed
REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 19990115

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
REG Reference to a national code

Ref country code: GB

Ref legal event code: IF02

REG Reference to a national code

Ref country code: CH

Ref legal event code: PFA

Owner name: BAYER CORPORATION

Free format text: BAYER CORPORATION#100 BAYER ROAD#PITTSBURGH, PA 15205-9741 (US) -TRANSFER TO- BAYER CORPORATION#100 BAYER ROAD#PITTSBURGH, PA 15205-9741 (US)

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DK

Payment date: 20110826

Year of fee payment: 19

Ref country code: CH

Payment date: 20110825

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20120831

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20120829

Year of fee payment: 20

Ref country code: MC

Payment date: 20120801

Year of fee payment: 20

Ref country code: IE

Payment date: 20120827

Year of fee payment: 20

Ref country code: GB

Payment date: 20120828

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 20120830

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20120829

Year of fee payment: 20

Ref country code: FR

Payment date: 20120830

Year of fee payment: 20

Ref country code: BE

Payment date: 20120827

Year of fee payment: 20

Ref country code: IT

Payment date: 20120823

Year of fee payment: 20

Ref country code: ES

Payment date: 20120827

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PT

Payment date: 20120216

Year of fee payment: 20

Ref country code: NL

Payment date: 20120825

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20120801

Year of fee payment: 20

REG Reference to a national code

Ref country code: DE

Ref legal event code: R071

Ref document number: 69321909

Country of ref document: DE

REG Reference to a national code

Ref country code: DK

Ref legal event code: EUP

REG Reference to a national code

Ref country code: PT

Ref legal event code: MM4A

Free format text: MAXIMUM VALIDITY LIMIT REACHED

Effective date: 20130816

REG Reference to a national code

Ref country code: NL

Ref legal event code: V4

Effective date: 20130816

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

BE20 Be: patent expired

Owner name: *BAYER CORP.

Effective date: 20130816

REG Reference to a national code

Ref country code: GB

Ref legal event code: PE20

Expiry date: 20130815

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK07

Ref document number: 172880

Country of ref document: AT

Kind code of ref document: T

Effective date: 20130816

REG Reference to a national code

Ref country code: GR

Ref legal event code: MA

Ref document number: 990400060

Country of ref document: GR

Effective date: 20130817

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20130817

Ref country code: PT

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20130823

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20130815

REG Reference to a national code

Ref country code: IE

Ref legal event code: MK9A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20130816

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20140925

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20130817